The lungs exist in a delicate balance between toxic oxidants and the protective activities of antioxidant defense systems. An imbalance in this system, either through an increase in oxidants or a dysfunction of the protective antioxidant defense systems, can lead to pathophysiological events in the lung causing pulmonary dysfunction. One type of pulmonary dysfunction in which an increase in oxidants can contribute is respiratory distress syndrome (RDS).
Infantile respiratory distress syndrome is a leading cause of death in the first 28 days of life. It strikes 1 in 100 babies worldwide and about 10 percent die. The syndrome rarely occurs in term infants but is generally associated with immaturity and low-birth weight (under 2 kg). Adult RDS shows similar clinical characteristics and pathophysiology to the infantile disease and is managed in the intensive care facility in a similar fashion. The adult disease has diverse etiologies and results from lung insults such as diffuse infections, aspiration of the gastric contents, inhalation of irritants and toxins, and pulmonary edema arising from such sources as narcotic overdose.
RDS is correlated with an absence or dysfunction of the lung surfactant which coats the alveoli of the lungs where gas exchange occurs, and has been associated with oxygen centered free radicals known as oxidants such as superoxide radicals, hydroxyl radicals, hydrogen peroxide which can generate hydroxyl radicals, and lipid peroxides, which have been implicated in cellular injury (Heffner, et al., Am. Rev.Respir.Dis.104: 531-554 1989); (Halliwell, FASEB J. 1: 358-364 1987).
The synthetic lung surfactant polypeptides of the present invention, without the antioxidant moieties, have been described in U. S. Pat. application Ser. Nos. 282,795 filed Dec. 9, 1988 and U.S. Ser. No. 214,228 filed Jul. 1, 1988 which are incorporated herein by reference. However, it is an object of the present invention to provide an effective synthetic lung surfactant having antioxidant properties, i.e., the ability to inhibit oxidation of susceptible compounds into oxidants.
Some synthetic lung surfactant preparations have added therapeutic agents such as Vitamin E to surfactant preparations as a separate component (U.S. Pat. No. 4,765,987; PCT publication no. WO 90/11768; PCT publication no. WO 90/07469). However, in the present invention the antioxidants are not a separate component but are actually incorporated into a polypeptide. An advantage of incorporating the antioxidant into the polypeptide is that instead of having a three component mixture (lipid, polypeptide and antioxidant), a two component mixture is available. This can be a significant advantage in testing for efficacy for a marketable pharmaceutical where a variety of dosages and formulations must be tested for each component. Additionally, a two component formulation is easier to manufacture.
The polypeptides of the present invention may be used singly in mixtures with lipid or in combination in mixtures of lipid wherein the polypeptide comprises a minor component of the surfactant mixture. The composition of the present invention may be prepared in high purity and in a standardized fashion as it is a defined mixture of synthetic components. Also, the components are not derived from animal sources which minimizes the risk of contamination by viruses and bacteria.